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- JP2020503871A5 JP2020503871A5 JP2019537074A JP2019537074A JP2020503871A5 JP 2020503871 A5 JP2020503871 A5 JP 2020503871A5 JP 2019537074 A JP2019537074 A JP 2019537074A JP 2019537074 A JP2019537074 A JP 2019537074A JP 2020503871 A5 JP2020503871 A5 JP 2020503871A5
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Description
記載された投与経路及び投薬量は、熟練した医師が最適な投与経路及び投薬量を容易に決定することができるため、指針としてのみ意図される。用量は、様々なパラメータに従って、特に腫瘍の位置、腫瘍の大きさ、治療される患者の年齢、体重及び状態、並びに投与経路に従って決定され得る。好ましくは、ウイルスは、腫瘍又は体腔内への直接注射によって投与される。ウイルスはまた、血管内への注射によって投与され得る。最適な投与経路は、腫瘍の位置及び大きさに依存する。複数回の用量は、免疫学的又は臨床的効果を達成するために必要とされ得、これは、必要に応じて、典型的には、2日〜12週間の間隔、好ましくは3日〜3週間の間隔で投与される。治療されている腫瘍のタイプの応答速度及び特定の患者の応答、また、与えられ得る任意の併用療法に依存して、最大5年以上好ましくは最大1カ月〜2年間の反復投与が与えられ得る。
本発明は、例えば以下の実施形態を包含する:
[実施形態1]CTLA-4阻害剤をコードする腫瘍溶解性ウイルス。
[実施形態2]CTLA-4阻害剤がCTLA-4抗体又はその抗原結合断片である、実施形態1に記載のウイルス。
[実施形態3]断片がscFv分子を含む、実施形態2に記載のウイルス。
[実施形態4]断片が1以上のIgG1定常領域に連結されたscFv分子である、実施形態2に記載のウイルス。
[実施形態5]抗体又は断片が、IgG重鎖に連結された軽鎖可変領域を含む、実施形態2〜4のいずれかに記載のウイルス。
[実施形態6]抗体又は断片が、(a)配列番号1に示される軽鎖可変領域配列及び配列番号3に示される重鎖可変領域配列、又は(b)配列番号11に示される軽鎖可変領域配列及び配列番号12に示される重鎖可変領域配列を含む、実施形態2〜5のいずれかに記載のウイルス。
[実施形態7]抗体又は断片が、(a)配列番号9のアミノ酸配列、又は(b)配列番号14のアミノ酸配列を含む、実施形態6に記載のウイルス。
[実施形態8]抗体又は断片が、(a)配列番号10のヌクレオチド配列、又は(b)配列番号15のヌクレオチド配列によりコードされる、実施形態7に記載のウイルス。
[実施形態9]GM-CSFをコードする遺伝子をさらに含む、実施形態1〜8のいずれかに記載のウイルス。
[実施形態10]免疫共刺激経路活性化分子又は免疫共刺激経路活性化分子をコードする遺伝子をさらに含む、実施形態1〜9のいずれかに記載のウイルス。
[実施形態11]免疫共刺激経路活性化分子をコードする遺伝子が、CD40リガンド(CD40L)、ICOSリガンド、GITRリガンド、4-1-BBリガンド、OX40リガンド、TL1A、CD30リガンド、CD27若しくはflt3リガンド又はこれらのいずれかの改変バージョンをコードする、実施形態10に記載のウイルス。
[実施形態12]免疫共刺激経路活性化分子をコードする遺伝子が、CD40リガンド、GITRリガンド、4-1-BBリガンド、OX40リガンド、ICOSリガンド、又はこれらのいずれかの改変バージョンをコードする、実施形態10又は11に記載のウイルス。
[実施形態13]融合誘導性タンパク質をコードする遺伝子をさらに含む、実施形態1〜12のいずれかに記載のウイルス。
[実施形態14]融合誘導性タンパク質が、水疱性口内炎ウイルス(VSV)Gタンパク質、シンシチン-1、シンシチン-2、シミアンウイルス5(SV5)Fタンパク質、麻疹ウイルス(MV)Hタンパク質、MV Fタンパク質、呼吸器合胞体ウイルス(RSV)Fタンパク質、及びRペプチドが欠失しているテナガザル(gibbon ape)白血病ウイルス(GALV)、マウス白血病ウイルス(MLV)、Mason-Pfizerサルウイルス(MPMV)又はウマ感染性貧血ウイルス(EIAV)由来の糖タンパク質からなる群から選択される、実施形態13に記載のウイルス。
[実施形態15]融合誘導性タンパク質が、テナガザル白血病ウイルス(GALV)由来の糖タンパク質であり、R膜貫通ペプチドが突然変異又は除去されている(GALV-R-)、実施形態13又は14に記載のウイルス。
[実施形態16]1つ以上の免疫共刺激経路活性化分子をコードする、実施形態1〜15のいずれかに記載のウイルス。
[実施形態17]ウイルスの臨床分離株に由来する、実施形態1〜16のいずれかに記載のウイルス。
[実施形態18]2つ以上の腫瘍細胞株を、同種のウイルスの1つ以上の参照臨床分離株よりも、インビトロで迅速に及び/又は低用量で死滅させる、ウイルスの改変された臨床分離株である、実施形態1〜17のいずれかに記載のウイルス。
[実施形態19]ヘルペスウイルス、ポックスウイルス、アデノウイルス、レトロウイルス、ラブドウイルス、パラミクソウイルス及びレオウイルスからなる群から選択される、実施形態1〜18のいずれかに記載のウイルス。
[実施形態20]単純ヘルペスウイルス(HSV)である、実施形態1〜19のいずれかに記載のウイルス。
[実施形態21]HSV1である、実施形態20に記載のウイルス。
[実施形態22]HSVが、
(a)機能的ICP34.5を発現しない、
(b)機能的ICP47を発現しない、及び/又は
(c)US11遺伝子を前初期遺伝子として発現する、
実施形態21に記載のウイルス。
[実施形態23]抗CTLA-4阻害剤タンパク質をコードする遺伝子が、挿入、部分的欠失、又は完全な欠失によって、ICP34.5をコードする遺伝子座に挿入されている、実施形態20〜22のいずれかに記載のウイルス。
[実施形態24]抗CTLA-4阻害剤タンパク質をコードする遺伝子が、GM-CSFなどの1以上の免疫刺激遺伝子及び/又は免疫共刺激経路活性化分子をコードする遺伝子及び/又は融合誘導性タンパク質をコードする遺伝子も含むカセットに含まれている、実施形態23に記載のウイルス。
[実施形態25]CTLA-4阻害剤をコードする配列、GM-CSFをコードする配列、免疫共刺激経路活性化分子をコードする配列及び/又は融合誘導性タンパク質をコードする遺伝子が、標的細胞における発現レベルを増加させるようにコドン最適化されている、実施形態1〜24のいずれかに記載のウイルス。
[実施形態26]3つの異種遺伝子を発現し、3つの異種遺伝子の各々が、CMVプロモーター、RSVプロモーター、SV40プロモーター(配列番号)及びレトロウイルスLTRプロモーターから選択される異なるプロモーターによって駆動される、実施形態1〜25のいずれかに記載のウイルス。
[実施形態27]CMVプロモーター、RSVプロモーター、SV40プロモーター及びレトロウイルスLTRプロモーターの各々によってそれぞれ駆動される4つの異種遺伝子を発現する、実施形態26に記載のウイルス。
[実施形態28]レトロウイルスLTRがMMLV(配列番号)由来である、実施形態26又は27に記載のウイルス。
[実施形態29]3つの異種遺伝子を発現し、3つの異種遺伝子の各々が、BGH、SV40、HGH及びRBGポリアデニル化配列から選択される異なるポリアデニル化配列によって終結される、実施形態1〜28のいずれかに記載のウイルス。
[実施形態30]BGH、SV40、HGH及びRBGポリアデニル化配列の各々によってそれぞれ終結される4つの異種遺伝子を発現する、実施形態29に記載のウイルス。
[実施形態31]ポックスウイルスである、実施形態26〜30のいずれかに記載のウイルス。
[実施形態32]実施形態1〜31のいずれかに記載のウイルス及び医薬として許容される担体又は希釈剤を含む医薬組成物。
[実施形態33]療法によってヒト又は動物の体を治療する方法に使用するための、実施形態1〜31のいずれかに記載のウイルス。
[実施形態34]がんを治療する方法に使用するための、実施形態1〜31のいずれかに記載のウイルス。
[実施形態35]方法が、さらなる抗がん剤を投与することを含む、実施形態34に記載の使用のためのウイルス。
[実施形態36]さらなる抗がん剤が、免疫共阻害経路又は免疫共刺激経路を標的とする薬剤、放射線療法及び/又は化学療法、腫瘍において生じる特定の遺伝子突然変異を標的とする薬剤、1つ以上の腫瘍抗原又はネオ抗原に対する免疫応答を誘導することが意図された薬剤、T細胞又はNK細胞に由来する細胞生成物、STING、cGAS、TLR又は他の自然免疫応答及び/若しくは炎症経路を刺激することが意図された薬剤、第2のウイルス、場合により腫瘍溶解性ウイルス、並びにそれらの組み合わせから選択される、実施形態35に記載の使用のためのウイルス。
[実施形態37]免疫共阻害経路を標的とする薬剤が、PD-1阻害剤、PD-L1阻害剤、LAG-3阻害剤、TIM-3阻害剤、VISTA阻害剤、aCSF1R阻害剤、IDO阻害剤、KIR阻害剤、SLAMF7阻害剤、CEACAM1阻害剤若しくはCD47阻害剤であり、及び/又は免疫共刺激経路を標的とする薬剤が、GITRアゴニスト、4-1-BBアゴニスト、OX40アゴニスト、CD40アゴニスト若しくはICOSアゴニストである、実施形態36に記載の使用のためのウイルス。
[実施形態38]さらなる抗がん剤が抗体である、実施形態35〜37のいずれかに記載の使用のためのウイルス。
[実施形態39]方法が、インドールアミン2,3-ジオキシゲナーゼ(IDO)経路の阻害剤及び免疫共阻害経路のさらなるアンタゴニスト、又は免疫共刺激経路のさらなるアゴニストを投与することを含む、実施形態35〜38のいずれかに記載の使用のためのウイルス。
[実施形態40]ウイルス及びさらなる抗がん剤が別々に投与される、実施形態34〜39のいずれかに記載の使用のためのウイルス。
[実施形態41]ウイルス及びさらなる抗がん剤が同時に投与される、実施形態34〜39のいずれかに記載の使用のためのウイルス。
[実施形態42]がんが固形腫瘍である、実施形態34〜41のいずれかに記載の使用のためのウイルス。
[実施形態43]実施形態1〜31のいずれかに記載のウイルスを滅菌バイアル、アンプル又はシリンジ中に含む製造物。
[実施形態44]治療有効量の実施形態1〜31のいずれかに記載のウイルス又は実施形態32に記載の医薬組成物を、それを必要とする患者に投与することを含む、がんを治療する方法。
[実施形態45]治療有効量のさらなる抗がん剤を、それを必要とする患者に投与することをさらに含む、実施形態44に記載の方法。
[実施形態46]さらなる抗がん剤が、免疫共阻害経路又は免疫共刺激経路を標的とする薬剤、放射線療法及び/又は化学療法、腫瘍において生じる特定の遺伝子突然変異を標的とする薬剤、1つ以上の腫瘍抗原又はネオ抗原に対する免疫応答を誘導することが意図された薬剤、T細胞又はNK細胞に由来する細胞生成物、STING、cGAS、TLR又は他の自然免疫応答及び/若しくは炎症経路を刺激することが意図された薬剤、第2のウイルス、場合により腫瘍溶解性ウイルス、並びにそれらの組み合わせからなる群から選択される、実施形態45に記載の方法。
[実施形態47]免疫共阻害経路を標的とする薬剤が、PD-1阻害剤、PD-L1阻害剤、LAG-3阻害剤、TIM-3阻害剤、VISTA阻害剤、aCSF1R阻害剤、IDO阻害剤、KIR阻害剤、SLAMF7阻害剤、CEACAM1阻害剤若しくはCD47阻害剤であり、及び/又は免疫共刺激経路を標的とする薬剤が、GITRアゴニスト、4-1-BBアゴニスト、OX40アゴニスト、CD40アゴニスト若しくはICOSアゴニストである、実施形態46に記載の方法。
[実施形態48]さらなる抗がん剤が抗体を含む、実施形態45〜47のいずれかに記載の方法。
[実施形態49]ウイルス及びさらなる抗がん剤が別々に投与される、実施形態45〜48のいずれかに記載の方法。
[実施形態50]ウイルス及びさらなる抗がん剤が同時に投与される、実施形態45〜48のいずれかに記載の方法。
[実施形態51]がんが固形腫瘍である、実施形態44〜50のいずれかに記載の方法。
[実施形態52]がんを治療する方法において使用するための医薬の製造における、実施形態1〜31のいずれかに記載のウイルスの使用。
[実施形態53]方法が、さらなる抗がん剤を投与することを含む、実施形態52に記載の使用。
The routes of administration and dosages described are intended only as guidelines, as a skilled physician can easily determine the optimal route of administration and dosage. The dose can be determined according to various parameters, especially the location of the tumor, the size of the tumor, the age, weight and condition of the patient being treated, and the route of administration. Preferably, the virus is administered by direct injection into the tumor or body cavity. The virus can also be administered by intravascular injection. The optimal route of administration depends on the location and size of the tumor. Multiple doses may be required to achieve an immunological or clinical effect, which will typically be at intervals of 2 days to 12 weeks, preferably 3 days to 3 days, as needed. Administered at weekly intervals. Depending on the response rate of the type of tumor being treated and the response of the particular patient, as well as any combination therapy that may be given, repeated doses of up to 5 years or more, preferably up to 1 month to 2 years may be given. ..
The present invention includes, for example, the following embodiments:
[Embodiment 1] An oncolytic virus encoding a CTLA-4 inhibitor.
[Embodiment 2] The virus according to Embodiment 1, wherein the CTLA-4 inhibitor is a CTLA-4 antibody or an antigen-binding fragment thereof.
[Embodiment 3] The virus according to embodiment 2, wherein the fragment contains an scFv molecule.
[Embodiment 4] The virus according to embodiment 2, wherein the fragment is an scFv molecule linked to one or more IgG1 constant regions.
[Embodiment 5] The virus according to any of embodiments 2 to 4, wherein the antibody or fragment comprises a light chain variable region linked to an IgG heavy chain.
[Embodiment 6] The antibody or fragment is (a) the light chain variable region sequence shown in SEQ ID NO: 1 and the heavy chain variable region sequence shown in SEQ ID NO: 3, or (b) the light chain variable shown in SEQ ID NO: 11. The virus according to any of embodiments 2-5, comprising the region sequence and the heavy chain variable region sequence set forth in SEQ ID NO: 12.
[Embodiment 7] The virus according to embodiment 6, wherein the antibody or fragment comprises (a) the amino acid sequence of SEQ ID NO: 9 or (b) the amino acid sequence of SEQ ID NO: 14.
[Embodiment 8] The virus according to embodiment 7, wherein the antibody or fragment is encoded by (a) the nucleotide sequence of SEQ ID NO: 10 or (b) the nucleotide sequence of SEQ ID NO: 15.
[Embodiment 9] The virus according to any one of embodiments 1 to 8, further comprising a gene encoding GM-CSF.
[Embodiment 10] The virus according to any one of embodiments 1 to 9, further comprising an immunoco-stimulation pathway activating molecule or a gene encoding an immunocostimulation pathway activating molecule.
[Embodiment 11] The gene encoding the immunoco-stimulation pathway activating molecule is CD40 ligand (CD40L), ICOS ligand, GITR ligand, 4-1-BB ligand, OX40 ligand, TL1A, CD30 ligand, CD27 or flt3 ligand or The virus according to embodiment 10, which encodes a modified version of any of these.
[Embodiment 12] An embodiment in which a gene encoding an immunoco-stimulation pathway activating molecule encodes a CD40 ligand, a GITR ligand, a 4-1-BB ligand, an OX40 ligand, an ICOS ligand, or a modified version thereof. The virus according to form 10 or 11.
[Embodiment 13] The virus according to any one of embodiments 1 to 12, further comprising a gene encoding a fusion-inducible protein.
[Embodiment 14] Fusion-inducing proteins include vesicular stomatitis virus (VSV) G protein, cincitin-1, cincitin-2, simianvirus 5 (SV5) F protein, measles virus (MV) H protein, MV F protein, Respiratory follicles virus (RSV) F protein and R peptide deficient in tenaga monkey (gibbon ape) leukemia virus (GALV), mouse leukemia virus (MLV), Mason-Pfizer monkey virus (MPMV) or horse infectivity 13. The virus of embodiment 13, selected from the group consisting of glycoproteins derived from anemia virus (EIAV).
[Embodiment 15] The fusion-inducing protein is a glycoprotein derived from gibbon ape leukemia virus (GALV), and the R transmembrane peptide is mutated or removed (GALV-R-), according to embodiment 13 or 14. Virus.
[Embodiment 16] The virus according to any one of embodiments 1 to 15, which encodes one or more immunoco-stimulatory pathway activating molecules.
[Embodiment 17] The virus according to any one of embodiments 1 to 16, which is derived from a clinical isolate of the virus.
[Embodiment 18] A modified clinical isolate of a virus that kills two or more tumor cell lines faster and / or at a lower dose in vitro than one or more reference clinical isolates of the same virus. The virus according to any one of embodiments 1 to 17.
[Embodiment 19] The virus according to any one of embodiments 1 to 18, selected from the group consisting of herpesvirus, poxvirus, adenovirus, retrovirus, rabdovirus, paramixovirus and leovirus.
[Embodiment 20] The virus according to any one of embodiments 1 to 19, which is a herpes simplex virus (HSV).
[Embodiment 21] The virus according to embodiment 20, which is HSV1.
[Embodiment 22] HSV
(a) Do not express functional ICP34.5,
(b) Do not express functional ICP47 and / or
(c) Express the US11 gene as a pre-early gene,
The virus according to embodiment 21.
[Embodiment 23] A gene encoding an anti-CTLA-4 inhibitor protein has been inserted into the locus encoding ICP34.5 by insertion, partial deletion, or complete deletion, embodiments 20- The virus described in any of 22.
[Embodiment 24] The gene encoding the anti-CTLA-4 inhibitor protein is a gene encoding one or more immunostimulatory genes such as GM-CSF and / or an immunoco-stimulatory pathway activating molecule and / or a fusion-inducing protein. 23. The virus according to embodiment 23, which is contained in a cassette that also contains a gene encoding.
[Embodiment 25] A sequence encoding a CTLA-4 inhibitor, a sequence encoding GM-CSF, a sequence encoding an immunoco-stimulation pathway activating molecule, and / or a gene encoding a fusion-inducible protein are present in a target cell. The virus according to any of embodiments 1-24, which is codon-optimized to increase expression levels.
[Embodiment 26] An embodiment in which three heterologous genes are expressed, each of the three heterologous genes being driven by a different promoter selected from the CMV promoter, RSV promoter, SV40 promoter (SEQ ID NO:) and retrovirus LTR promoter. The virus according to any of forms 1 to 25.
[Embodiment 27] The virus according to embodiment 26, which expresses four heterologous genes driven by each of the CMV promoter, RSV promoter, SV40 promoter and retrovirus LTR promoter.
[Embodiment 28] The virus according to embodiment 26 or 27, wherein the retrovirus LTR is derived from MMLV (SEQ ID NO:).
[Embodiment 29] Of Embodiments 1-28, which expresses three heterologous genes, each of which is terminated by a different polyadenylation sequence selected from BGH, SV40, HGH and RBG polyadenylation sequences. The virus described in either.
[Embodiment 30] The virus of embodiment 29, which expresses four heterologous genes, each terminated by each of the BGH, SV40, HGH and RBG polyadenylation sequences.
[Embodiment 31] The virus according to any one of embodiments 26 to 30, which is a poxvirus.
[Embodiment 32] A pharmaceutical composition comprising the virus according to any one of embodiments 1 to 31 and a pharmaceutically acceptable carrier or diluent.
[Embodiment 33] The virus according to any of embodiments 1-31 for use in methods of treating the human or animal body by therapy.
[Embodiment 34] The virus according to any one of embodiments 1-31 for use in a method of treating cancer.
[Embodiment 35] The virus for use according to embodiment 34, wherein the method comprises administering an additional anti-cancer agent.
[Embodiment 36] Additional anti-cancer agents target immunoco-inhibition or immunoco-stimulation pathways, radiotherapy and / or chemotherapy, agents targeting specific gene mutations that occur in tumors, 1 Drugs intended to induce an immune response against one or more tumor or neoantigens, cell products derived from T or NK cells, STING, cGAS, TLR or other spontaneous immune responses and / or inflammatory pathways. The virus for use according to embodiment 35, which is selected from a drug intended to stimulate, a second virus, optionally an oncolytic virus, and a combination thereof.
[Embodiment 37] Drugs that target the immunoco-inhibition pathway include PD-1 inhibitors, PD-L1 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, VISTA inhibitors, aCSF1R inhibitors, and IDO inhibitors. Agents, KIR inhibitors, SLAMF7 inhibitors, CEACAM1 inhibitors or CD47 inhibitors, and / or agents that target the immunoco-stimulation pathway are GITR agonists, 4-1-BB agonists, OX40 agonists, CD40 agonists or The virus for use according to embodiment 36, which is an ICOS agonist.
[Embodiment 38] The virus for use according to any of embodiments 35-37, wherein the further anti-cancer agent is an antibody.
[Embodiment 39] The method comprises administering an inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway and a further antagonist of the immunoco-inhibition pathway, or a further agonist of the immunoco-stimulation pathway. Virus for use described in any of ~ 38.
[Embodiment 40] The virus for use according to any of embodiments 34-39, wherein the virus and additional anti-cancer agents are administered separately.
[Embodiment 41] The virus for use according to any of embodiments 34-39, wherein the virus and additional anti-cancer agents are co-administered.
[Embodiment 42] The virus for use according to any of embodiments 34-41, wherein the cancer is a solid tumor.
[Embodiment 43] A product containing the virus according to any one of embodiments 1 to 31 in a sterile vial, ampoule or syringe.
[Embodiment 44] Treatment of cancer, which comprises administering a therapeutically effective amount of the virus according to any of embodiments 1-31 or the pharmaceutical composition according to embodiment 32 to a patient in need thereof. how to.
[Embodiment 45] The method of embodiment 44, further comprising administering a therapeutically effective amount of an additional anti-cancer agent to a patient in need thereof.
[Embodiment 46] Additional anti-cancer agents target immunoco-inhibition or immunoco-stimulation pathways, radiation therapy and / or chemotherapy, agents targeting specific gene mutations that occur in tumors, 1 Drugs intended to induce an immune response against one or more tumor or neoantigens, cell products derived from T or NK cells, STING, cGAS, TLR or other innate immune responses and / or inflammatory pathways. 45. The method of embodiment 45, which is selected from the group consisting of a drug intended to stimulate, a second virus, optionally an oncolytic virus, and a combination thereof.
[Embodiment 47] Drugs that target the immunoco-inhibition pathway include PD-1 inhibitors, PD-L1 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, VISTA inhibitors, aCSF1R inhibitors, and IDO inhibitors. Agents, KIR inhibitors, SLAMF7 inhibitors, CEACAM1 inhibitors or CD47 inhibitors, and / or agents that target the immunoco-stimulation pathway are GITR agonists, 4-1-BB agonists, OX40 agonists, CD40 agonists or The method of embodiment 46, which is an ICOS agonist.
[Embodiment 48] The method according to any of embodiments 45-47, wherein the further anti-cancer agent comprises an antibody.
[Embodiment 49] The method of any of embodiments 45-48, wherein the virus and additional anti-cancer agents are administered separately.
[Embodiment 50] The method according to any of embodiments 45-48, wherein the virus and additional anti-cancer agent are administered simultaneously.
[Embodiment 51] The method according to any of embodiments 44-50, wherein the cancer is a solid tumor.
[Embodiment 52] Use of the virus according to any of embodiments 1-31 in the manufacture of a medicament for use in a method of treating cancer.
[Embodiment 53] The use according to embodiment 52, wherein the method comprises administering an additional anti-cancer agent.
Claims (22)
(a)配列番号1に示される軽鎖可変領域配列及び配列番号3に示される重鎖可変領域配列を含む;
(b)配列番号11に示される軽鎖可変領域配列及び配列番号12に示される重鎖可変領域配列を含む;
(c)配列番号9のアミノ酸配列を含む;
(d)配列番号14のアミノ酸配列を含む;
(e)配列番号10のヌクレオチド配列によりコードされる;又は
(f)配列番号15のヌクレオチド配列によりコードされる、
請求項2又は3に記載のウイルス。 The antibody or fragment
(A) Includes the light chain variable region sequence set forth in SEQ ID NO: 1 and the heavy chain variable region sequence set forth in SEQ ID NO: 3;
(B) Includes the light chain variable region sequence set forth in SEQ ID NO: 11 and the heavy chain variable region sequence set forth in SEQ ID NO: 12;
(C) Contains the amino acid sequence of SEQ ID NO: 9;
(D) Contains the amino acid sequence of SEQ ID NO: 14;
(E) Encoded by the nucleotide sequence of SEQ ID NO: 10; or (f) Encoded by the nucleotide sequence of SEQ ID NO: 15.
The virus according to claim 2 or 3.
(b)免疫共刺激経路活性化分子又は免疫共刺激経路活性化分子をコードする遺伝子;及び/又は
(c)融合誘導性タンパク質をコードする遺伝子
をさらに含む、請求項1〜4のいずれか1項に記載のウイルス。 (A) Gene encoding GM-CSF;
Any 1 of claims 1 to 4, further comprising (b) a gene encoding an immunoco-stimulatory pathway-activating molecule or an immuno-co-stimulating pathway-activating molecule; and / or (c) a gene encoding a fusion-inducible protein. The virus described in the section.
(b)融合誘導性タンパク質が、水疱性口内炎ウイルス(VSV)Gタンパク質、シンシチン-1、シンシチン-2、シミアンウイルス5(SV5)Fタンパク質、麻疹ウイルス(MV)Hタンパク質、MV Fタンパク質、呼吸器合胞体ウイルス(RSV)Fタンパク質、及びRペプチドが欠失しているテナガザル(gibbon ape)白血病ウイルス(GALV)、マウス白血病ウイルス(MLV)、Mason-Pfizerサルウイルス(MPMV)若しくはウマ感染性貧血ウイルス(EIAV)由来の糖タンパク質からなる群から選択される;並びに/又は
(c)融合誘導性タンパク質が、テナガザル白血病ウイルス(GALV)由来の糖タンパク質であり、R膜貫通ペプチドが突然変異若しくは除去されている(GALV-R-)、
請求項5に記載のウイルス。 (A) The gene encoding the immunoco-stimulatory pathway activating molecule encodes CD40 ligand (CD40L), ICOS ligand, GITR ligand, 4-1-BB ligand, OX40 ligand, TL1A, CD30 ligand, CD27 or flt3 ligand. ;
(B) Fusion-inducing proteins are bullous stomatitis virus (VSV) G protein, cincitin-1, cincitin-2, simianvirus 5 (SV5) F protein, measles virus (MV) H protein, MV F protein, respiratory organs. Gibbon ape leukemia virus (GALV), murine leukemia virus (MLV), Mason-Pfizer monkey virus (MPMV) or horse-infectious anemia virus lacking the F protein (RSV) F protein and R peptide Selected from the group consisting of (EIAV) -derived glycoproteins; and / or (c) the fusion-inducible protein is a tenagazal leukemia virus (GALV) -derived glycoprotein in which the R-membrane peptide is mutated or removed. (GALV-R-),
The virus according to claim 5.
(b)2つ以上の腫瘍細胞株を、同種のウイルスの1つ以上の参照臨床分離株よりも、インビトロで迅速に及び/若しくは低用量で死滅させる、ウイルスの改変された臨床分離株である;並びに/又は
(c)ヘルペスウイルス、ポックスウイルス、アデノウイルス、レトロウイルス、ラブドウイルス、パラミクソウイルス及びレオウイルスからなる群から選択される、
請求項1〜7のいずれか1項に記載のウイルス。 (A) Derived from a clinical isolate of the virus;
(B) A modified clinical isolate of the virus that kills two or more tumor cell lines faster and / or at lower doses in vitro than one or more reference clinical isolates of the same virus. And / or (c) selected from the group consisting of herpesvirus, poxvirus, adenovirus, retrovirus, rabdovirus, paramixovirus and leovirus.
The virus according to any one of claims 1 to 7.
(ii)HSV1である;又は
(iii)HSVが、
(a)機能的ICP34.5を発現しない、
(b)機能的ICP47を発現しない、及び/若しくは
(c)US11遺伝子を前初期遺伝子として発現する、
請求項1〜8のいずれか1項に記載のウイルス。 (I) Herpes simplex virus (HSV);
(Ii) HSV1; or (iii) HSV,
(a) Do not express functional ICP34.5,
(b) Do not express functional ICP47 and / or
(c) Express the US11 gene as a pre-early gene,
The virus according to any one of claims 1 to 8.
(b)GM-CSFなどの1以上の免疫刺激遺伝子及び/若しくは免疫共刺激経路活性化分子をコードする遺伝子及び/若しくは融合誘導性タンパク質をコードする遺伝子も含むカセットに含まれている抗CTLA-4阻害剤タンパク質をコードする遺伝子が、挿入、部分的欠失、若しくは完全な欠失によって、ICP34.5をコードする遺伝子座に挿入されている、
請求項9に記載のウイルス。 (A) The gene encoding the anti-CTLA-4 inhibitor protein has been inserted at the locus encoding ICP34.5 by insertion, partial deletion, or complete deletion; or (b) GM- An anti-CTLA-4 inhibitor protein contained in a cassette that also contains one or more immunostimulatory genes such as CSF and / or genes encoding immunoco-stimulatory pathway activating molecules and / or genes encoding fusion-inducible proteins. The encoding gene has been inserted at the locus encoding ICP34.5 by insertion, partial deletion, or complete deletion,
The virus according to claim 9.
(a)さらなる抗がん剤をウイルスと同時に又は別々に投与すること;
(b)さらなる抗がん剤をウイルスと同時に又は別々に投与することであって、さらなる抗がん剤が、PD-1阻害剤、PD-L1阻害剤、LAG-3阻害剤、TIM-3阻害剤、VISTA阻害剤、aCSF1R阻害剤、IDO阻害剤、KIR阻害剤、SLAMF7阻害剤、CEACAM1阻害剤若しくはCD47阻害剤などの免疫共阻害経路を標的とする薬剤、GITRアゴニスト、4-1-BBアゴニスト、OX40アゴニスト、CD40アゴニスト若しくはICOSアゴニストなどの免疫共刺激経路を標的とする薬剤、放射線療法及び/又は化学療法、腫瘍において生じる特定の遺伝子突然変異を標的とする薬剤、1つ以上の腫瘍抗原又はネオ抗原に対する免疫応答を誘導することが意図された薬剤、T細胞又はNK細胞に由来する細胞生成物、STING、cGAS、TLR又は他の自然免疫応答及び/若しくは炎症経路を刺激することが意図された薬剤、第2のウイルス、場合により腫瘍溶解性ウイルス、並びにそれらの組み合わせから選択される;
(c)さらなる抗がん剤をウイルスと同時に又は別々に投与することであって、さらなる抗がん剤が抗体である;又は
(d)インドールアミン2,3-ジオキシゲナーゼ(IDO)経路の阻害剤及び免疫共阻害経路のさらなるアンタゴニスト、又は免疫共刺激経路のアゴニストを投与すること
を含む、請求項17に記載の組成物。 The method is
(A) Administration of additional anticancer drugs simultaneously or separately from the virus;
(B) Administration of additional anti-cancer agents simultaneously with or separately from the virus, where additional anti-cancer agents are PD-1 inhibitors, PD-L1 inhibitors, LAG-3 inhibitors, TIM-3 Drugs that target immune co-inhibitory pathways such as inhibitors, VISTA inhibitors, aCSF1R inhibitors, IDO inhibitors, KIR inhibitors, SLAMF7 inhibitors, CEACAM1 inhibitors or CD47 inhibitors, GITR agonists, 4-1-BB Drugs that target immune co-stimulatory pathways such as agonists, OX40 agonists, CD40 agonists or ICOS agonists, radiotherapy and / or chemotherapy, drugs that target specific gene mutations that occur in tumors, one or more tumor antigens Or drugs intended to induce an immune response against neoantigens, cell products derived from T or NK cells, STING, cGAS, TLR or other innate immune responses and / or intended to stimulate inflammatory pathways. Selected from the drugs used, the second virus, and possibly the tumor-soluble virus, and combinations thereof;
(C) Additional anti-cancer agents are administered simultaneously with or separately from the virus, where additional anti-cancer agents are antibodies; or (d) inhibition of the indoleamine 2,3-dioxygenase (IDO) pathway. The composition according to claim 17, comprising administering an agent and a further antagonist of the immuno-co-inhibition pathway, or an agonist of the immuno-co-stimulation pathway.
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CN110218707B (en) * | 2019-05-29 | 2021-10-22 | 上海市公共卫生临床中心 | Novel oncolytic virus and preparation method and application thereof |
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GB0317511D0 (en) * | 2003-07-25 | 2003-08-27 | Biovex Ltd | Viral vectors |
AU2007241023B2 (en) | 2006-03-30 | 2013-11-28 | University Of California | Methods and compositions for localized secretion of anti-CTLA-4 antibodies |
EP2879498A4 (en) * | 2012-07-30 | 2016-03-30 | Alex Wah Hin Yeung | Live and in-vivo tumor specific cancer vaccine system developed by co-administration of either at least two or all three of the following components such as tumor cells, an oncolytic virus vector with transgenic expression of gm-csf and an immune checkpoint modulator |
US9789182B2 (en) * | 2012-10-23 | 2017-10-17 | Bristol-Myers Squibb Company | Combination of anti-KIR and anti-CTLA-4 antibodies to treat cancer |
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KR102330183B1 (en) * | 2013-10-28 | 2021-11-23 | 유니버시티 오브 피츠버그-오브 더 커먼웰쓰 시스템 오브 하이어 에듀케이션 | Oncolytic hsv vector |
WO2015128313A1 (en) * | 2014-02-25 | 2015-09-03 | Deutsches Krebsforschungszentrum | Rna viruses for immunovirotherapy |
EP3169341B1 (en) * | 2014-07-16 | 2019-06-05 | Transgene SA | Oncolytic virus for expression of immune checkpoint modulators |
WO2017118867A1 (en) * | 2016-01-08 | 2017-07-13 | Replimune Limited | Use of an oncolytic virus for the treatment of cancer |
EP3380621A4 (en) * | 2016-04-22 | 2019-05-08 | Immvira Co., Limited | CONSTRUCTION OF ONCOLYTIC HERPES SIMPLEX VIRUSES (oHSV) OBLIGATE VECTOR AND CONSTRUCTS FOR CANCER THERAPY |
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2018
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